Endogenous Opioids, what`s that?

We are all naturally dependent on opioids for our emotional health. Both narcotics and internally generated endorphins exert their action on the body by interacting with specific membrane receptor-proteins on our nerve cells.

The body produces three large pro-compounds: proenkephalin, prodynorphin, and pro-opiomelanocortin. Endorphins can further decompose to small fragments, oligomers, which are still active. Oligomers pass the blood-brain barrier more readily. Enzymatic degradation of small-chain endorphins is accomplished by dipeptidyl carboxypeptidase, enkephalinases, angiotensinases, and other enzymes. This limits their lifetime in the unbound state.

Opioid receptors presynaptically inhibit transmission of excitatory pathways. These pathways include acetylcholine, the catecholamines, serotonin, and substance P. Substance P is a neuropeptide active in neurons that mediate our sense of pain; antagonists of substance P are currently under investigation as clinical antidepressants. Endorphins are also involved in glucose regulation. Opioid receptors are functionally designated as mu, delta, kappa, etc. These categories can be further sub-classified by function or structure. Decoding the human genome has allowed the genetic switching-mechanisms that control the expression of each opioid receptor to be determined at the transcriptional and post-transcriptional level.

All classes of opioid receptor share key similarities. Opioid-driven inhibition of neuronal excitability is mediated by the activation of a variety of potassium channels in the plasma membrane. The disparate subjective and behavioural effects evoked by activation of the different categories of opioid receptor are typically not the outcome of different cellular responses, but reflect the different anatomical distributions of each receptor. Unlike kappa opioid receptors, however, both mu and delta opioid receptors internalise on exposure to agonists. Activation of any type of opioid receptor inhibits adenylate cyclase, resulting in a fall in intracellular cAMP and diminished action potential firing. This causes a reduced flow of nociceptive information to the brain. Conversely, opioid addicts undergoing withdrawal suffer elevated cAMP levels and enhanced protein kinase A activity, resulting in increased neurotransmitter release.

The opioid receptors all have a common general structure. They are characteristically G protein-linked receptors embedded in the plasma membrane of neurons. Once the receptors are bound, a portion of the G protein is activated, allowing it to diffuse within the plasma membrane. The G protein moves within the membrane until it reaches its target – either an enzyme or an ion channel. These targets normally alter protein phosphorylation and/or gene transcription. Whereas protein phosphorylation alters short-term neuronal activity, gene transcription acts over a longer timescale.

Two new classes of opioid neuropeptide have recently been identified. These are nociceptin and the endomorphins.

Nociceptin (also known as orphanin) was first identified in 1995. It is the endogenous ligand of the opioid receptor-like 1 receptor. Depending dosage and site, nociceptin has subjectively extremely nasty hyperalgesic effects. Nociceptin receptor antagonists are candidate antidepressants and analgesics.

Endomorphin1 and endomorphin2 are newly-discovered ligands with the highest affinity and selectivity for the mu opioid receptor of all the endogenous opioids. Critically, endomorphin1 increases dopamine efflux in the nucleus accumbens via mu-1 opioid receptors. In the absence of selective endogenous mu-opioid receptor agonists, our vulnerability to pain and suffering would be even worse. Several novel, peripherally administered endomorphin1 analogues are under investigation that are more resistant to enzymatic hydrolysis. They should offer new opportunities for euphoric well-being, enriched mental health and more effective pain-relief.

Morphine itself is produced naturally by the human body and brain, albeit in much lower concentrations than in the opium poppy Papaver somniferum. Morphine is synthesised in human neuroblastoma cells via a biosynthetic route similar to that of the opium poppy. It is also present in healthy neurons, where it undergoes Ca2+-dependent release suggestive of a neurotransmitter or neuromodulator role. But the physiological role of endogenous morphine is still obscure.

Opioidergic neurons are particularly concentrated in the ventral tegmental area. The VTA is an important nerve tract in the limbic system. The VTA passes messages to clusters of nerve cells in the nucleus accumbens and the frontal cortex. This forms the brain’s primary reward pathway, the mesolimbic dopamine system. Its neurons are called dopaminergic because dopamine is manufactured, transported down the length of the neuron, and packaged for release into the synapses.

GABA normally plays a braking role on the dopaminergic cells. Opioids and endogenous opioid neurotransmitters activate the presynaptic opioid receptors on GABA neurons. This inhibits the release of GABA in the ventral tegmental area. Inhibiting GABA allows the dopaminergic neurons to fire more vigorously. The release of extra dopamine in the nucleus accumbens is intensely pleasurable.

Both delta opioid agonists and inhibitors of enkephalin catabolism have anxiolytic and antidepressant activity. Kappa opioid receptor antagonists have antidepressant activity; the first orally active selective kappa receptor antagonist is the investigational drug JDC-2. Mu receptor activation is crucial to the rewarding, analgesic and addictive properties of opioids. Government researchers and pharmaceutical companies are searching for powerful analgesics that won’t make the user feel happy [„high“] too.

Mu-receptors are found mainly in the brainstem and the medial thalamus. There are two primary sub-types: mu-1 and mu-2. More than 100 polymorphisms have been identified in the human mu opioid peptide receptor gene. Stimulation of the mu-1 receptors is primarily responsible for the beautiful sense of euphoria, serenity and analgesia induced by a potent and selective mu opioid agonist. Receptor activation by mu opioid agonists increases cell firing in the ventral tegmental area. This triggers dopamine release in the nucleus accumbens by reducing GABA’s tonic inhibitory control of the dopaminergic neurons. By contrast, at the height of the opioid withdrawal syndrome, typical firing rates and burst firings of VTA-nucleus accumbens neurons are reduced to around 30% of normal. The withdrawal syndrome can be quickly remedied by the administration of a potent mu agonist such as morphine. Care is needed: stimulation of the mu-2 opioid receptors helps modulate respiratory depression. For obvious reasons, this is potentially dangerous. The endogenous ligands for the mu opioid receptors have recently been discovered. They are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2).

Unfortunately, we still lack clinically available opioids specific to the mu-1 receptor. Their advent will (potentially) be a tremendous boon to mental and physical health.